etelcalcetide (Rx)

>10%

Decreased serum calcium, asymptomatic reductions in calcium <7.5 mg/dL or clinically significant asymptomatic reductions in corrected serum calcium between 7.5 and <8.3 mg/dL that required medical management (64%)

Muscle spasms (12%)

Diarrhea (11%)

Nausea (11%)

1-10%

Vomiting (9%)

Headache (8%)

Hypocalcemia (7%)

Paresthesia (6%)

Hypersensitivity (4.4%)

Hyperkalemia (4%)

Hospitalization for heart failure (2%)

Myalgia (2%)

QTc prolongation secondary to hypocalcemia (1.2%)

Hypophosphatemia (1%)

<1%

Hypocalcemia, symptomatic reductions in corrected serum calcium <8.3 mg/dL (0.2%)

Postmarketing Reports

Anaphylactic reaction

Seizures secondary to hypocalcemia

Contraindications

Hypersensitivity to etelcalcetide or any of its excipients

Cautions

Cases of hypotension, congestive heart failure, and decreased myocardial performance reported in clinical trials; reductions in corrected serum calcium may be associated with congestive heart failure, however, a causal relationship could not be completely excluded closely monitor for worsening signs and symptoms of heart failure

Adynamic bone may develop if PTH levels are chronically suppressed; if PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or etelcalcetide should be reduced or discontinued; after discontinuation, resume therapy at a lower dose to maintain PTH levels in the target range

Rare reports of upper GI bleeding occurred during clinical trials; the exact cause of the GI bleeds were unknown and there were too few cases to determine if GI bleeding was related to this medication; patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers, or severe vomiting) may be at increased risk for GI bleeding while receiving therapy; monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with this medication and for signs and symptoms of GI bleeding and ulcerations during therapy; promptly evaluate and treat any suspected GI bleeding

Hypocalcemia

• Etelcalcetide lowers serum calcium and can lead to hypocalcemia, sometimes severe; low serum calcium can cause paresthesias, myalgias, muscle spasms, seizures, QT interval prolongation, and ventricular arrhythmia
• Coadministration with another oral calcium-sensing receptor agonist could result in severe, life-threatening hypocalcemia; closely monitor corrected serum calcium in patients receiving etelcalcetide and concomitant therapies known to lower serum calcium
• Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to therapy; closely monitor corrected serum calcium and QT interval in patients at risk receiving therapy

• Significant reductions in corrected serum calcium may lower threshold for seizures; patients with a history of seizure disorder may be at increased risk for seizures if they develop hypocalcemia due to this medication; monitor corrected serum calcium in patients with seizure disorders receiving therapy

• Do not initiate in patients if corrected serum calcium is less than lower limit of normal; monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment; educate patients on symptoms of hypocalcemia and advise them to contact a healthcare provider if they occur

• If corrected serum calcium falls below lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration); dose reduction or discontinuation of therapy may be necessary

Pregnancy

There are no available data on the use in pregnant women

Animal studies

• In animal reproduction studies, effects were seen at doses associated with maternal toxicity that included hypocalcemia
• In a prenatal and postnatal study in rats administered etelcalcetide during organogenesis through delivery and weaning, there was a slight increase in perinatal pup mortality, delay in parturition, and transient effects on pup growth at exposures 1.8 times the human exposure for the clinical dose of 15 mg 3 times/week

Lactation

Unknown if distributed in human breast milk

Studies in rats showed distribution in milk at concentrations similar to plasma

Because of the potential for etelcalcetide to cause adverse effects in breastfed infants, including hypocalcemia, use is not recommended while breastfeeding

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Calcimimetic agent that allosterically modulates the calcium-sensing receptor (CaSR)

Etelcalcetide binds to the CaSR and enhances activation of the receptor by extracellular calcium

Activation of the CaSR on parathyroid chief cells decreases PTH secretion

Distribution

Protein bound: Predominately bound to plasma albumin by reversible covalent binding

Blood to plasma ratio: ~0.6

Vd: 796 L

Metabolism

Biotransformed in blood by reversible disulfide exchange with endogenous thiols to predominantly form conjugates with serum albumin

Not metabolized by CYP450 enzymes

Elimination

Half-life: 3-4 days

Excretion

• Normal renal function (volunteers in clinical trials): Cleared by renal excretion
• Hemodialysis: Removed with a hemodialysis clearance value of 7.66 L/hr

IV Preparation

Do not mix or dilute prior to administration

Solution is clear and colorless

Inspect for particulate matter and discoloration prior to administration

Do not use vial if particulate matter or discoloration is observed

IV Administration

Administer IV push into venous line of the dialysis circuit during rinse back or IV after rinse back; only administer at the end of hemodialysis treatment

Administered during rinse back: Administer a sufficient volume of 0.9% NaCl (eg, 150 mL) of rinse back into dialysis tubing

Administered after rinse back: Flush line with at least 10 mL of 0.9% NaCl

Missed dose

• If a regularly scheduled hemodialysis treatment is missed, DO NOT administer any missed doses
• Resume dose at the end of the next hemodialysis treatment at the prescribed dose
• If doses are missed for >2 weeks, reinitiate at the recommended starting dose of 5 mg (or 2.5 mg if that was the patient’s last dose)

Storage

Store in the original carton in refrigerator at 2-8°C (36-46°F) to protect from light

Once removed from the refrigerator

• Do not expose to temperatures >25°C (77°F)
• Use within 7 days if stored in the original carton
• Use within 4 hr and do not expose to direct sunlight if removed from the original carton